Deiodinases, organic anion transporter polypeptide polymorphisms and ischemic stroke outcomes

Published:September 11, 2019DOI:https://doi.org/10.1016/j.jns.2019.116457

      Highlights

      • Functional outcome after stroke is determined in part by genetic factors.
      • Stroke activates the thyroid axis, so we examined SNPs of DIO1–3 and OATP1C1.
      • DIO3 rs945006-T/G and OATP1C1 rs10770704-C/T predicted 1-year functional outcome.

      Abstract

      Background

      Ischemic stroke is a major cause of premature death and chronic disability worldwide, and individual variation in functional outcome is strongly influenced by genetic factors. Neuroendocrine signaling by the hypothalamic−hypophyseal−thyroid axis is a critical regulator of post-stroke pathogenesis, suggesting that allelic variants in thyroid hormone (TH) signaling can influence stroke outcome.
      Aim: To examine associations between acute ischemic stroke (AIS) outcome and allelic variants of the TH metabolizing enzymes deiodinase type 1–3 (DIO1–3) and membrane transporting organic anion polypeptide C1 (OATP1C1).

      Methods

      Eligible AIS patients from Lithuania (n = 248) were genotyped for ten DIO1–3 and OATP1C1 single nucleotide polymorphisms (SNPs): DIO1 rs12095080-A/G, rs11206244-C/T, and rs2235544-A/C; DIO2 rs225014-T/C and rs225015-G/A; DIO3 rs945006-T/G; OATP1C1 rs974453-G/A, rs10444412-T/C, rs10770704-C/T, and rs1515777-A/G. Functional outcome was evaluated one year after index AIS using the modified Rankin Scale. Analyses were adjusted for important confounders, including serum free triiodothyronine.

      Results

      After adjustment for potential confounders, the major allelic (wild-type) DIO3 genotype rs945006-TT was associated with better 1-year AIS functional outcome (odds ratio [OR] = 0.25; 95% confidence interval [CI]: 0.08–0.74; p = .013), while the wild-type OATP1C1 genotype rs10770704-CC was associated with poorer outcome (OR = 2.00, 95%CI: 1.04–3.86; p = .038).

      Conclusion

      Allelic variants in thyroid axis genes may prove useful for prognosis and treatment guidance.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • [Anonymous]
        Prevalence and most common causes of disability among adults—United States, 2005.
        MMWR Morb. Mortal. Wkly Rep. 2009; 58: 421-426
        • Feigin V.L.
        • Norrving B.
        • Mensah G.A.
        Global burden of stroke.
        Circ. Res. 2017; 120: 439-448https://doi.org/10.1161/circresaha.116.308413
        • Dirnagl U.
        • Iadecola C.
        • Moskowitz M.A.
        Pathobiology of ischaemic stroke: an integrated view.
        Trends Neurosci. 1999; 22: 391-397
        • Scott J.F.
        • Gray C.S.
        Cerebral and systemic pathophysiological responses to acute stroke.
        Age Ageing. 2000; 29: 197-202https://doi.org/10.1093/ageing/29.3.197
        • Jiang X.
        • Xing H.
        • Wu J.
        • et al.
        Prognostic value of thyroid hormones in acute ischemic stroke - a meta analysis.
        Sci. Rep. 2017; 716256https://doi.org/10.1038/s41598-017-16564-2
        • De Groot L.J.
        Dangerous dogmas in medicine: the nonthyroidal illness syndrome.
        J. Clin. Endocrinol. Metab. 1999; 84: 151-164https://doi.org/10.1210/jcem.84.1.5364
        • Fliers E.
        • Bianco A.C.
        • Langouche L.
        • et al.
        Thyroid function in critically ill patients.
        Lancet Diabetes Endocrinol. 2015; 3: 816-825https://doi.org/10.1016/s2213-8587(15)00225-9
        • Mendoza A.
        • Hollenberg A.N.
        New insights into thyroid hormone action.
        Pharmacol. Ther. 2017; 173: 135-145https://doi.org/10.1016/j.pharmthera.2017.02.012
        • Mondal S.
        • Raja K.
        • Schweizer U.
        Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones.
        55. 2016: 7606-7630https://doi.org/10.1002/anie.201601116
        • Bianco A.C.
        • Dumitrescu A.
        • Gereben B.
        • et al.
        Paradigms of dynamic control of thyroid hormone signaling.
        Endocr. Rev. 2019; 40: 1000-1047https://doi.org/10.1210/er.2018-00275
        • Freitas B.C.
        • Gereben B.
        • Castillo M.
        • et al.
        Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells.
        J. Clin. Invest. 2010; 120: 2206-2217https://doi.org/10.1172/jci41977
        • Landers K.
        • Richard K.
        Traversing barriers - how thyroid hormones pass placental, blood-brain and blood-cerebrospinal fluid barriers.
        Mol. Cell. Endocrinol. 2017; 458: 22-28https://doi.org/10.1016/j.mce.2017.01.041
        • Friesema E.C.
        • Grueters A.
        • Biebermann H.
        • et al.
        Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.
        Lancet. 2004; 364: 1435-1437https://doi.org/10.1016/s0140-6736(04)17226-7
        • Stromme P.
        • Groeneweg S.
        • Lima de Souza E.C.
        • et al.
        Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration.
        Thyroid. 2018; 28: 1406-1415https://doi.org/10.1089/thy.2018.0595
        • van der Deure W.M.
        • Appelhof B.C.
        • Peeters R.P.
        • et al.
        Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients.
        Clin. Endocrinol. 2008; 69: 804-811https://doi.org/10.1111/j.1365-2265.2008.03267.x
        • Gereben B.
        • Zavacki A.M.
        • Ribich S.
        • et al.
        Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling.
        Endocr. Rev. 2008; 29: 898-938https://doi.org/10.1210/er.2008-0019
        • Verloop H.
        • Dekkers O.M.
        • Peeters R.P.
        • et al.
        Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans.
        Eur. J. Endocrinol. 2014; 171: R123-R135https://doi.org/10.1530/eje-14-0302
        • Bianco A.C.
        • Kim B.S.
        Pathophysiological relevance of deiodinase polymorphism.
        Curr. Opin. Endocrinol. Diab. Obes. 2018; 25: 341-346https://doi.org/10.1097/med.0000000000000428
        • McAninch E.A.
        • Bianco A.C.
        The swinging pendulum in treatment for hypothyroidism: from (and toward?) combination therapy.
        Front. Endocrinol. (Lausanne). 2019; 10: 446https://doi.org/10.3389/fendo.2019.00446
        • McAninch E.A.
        • Rajan K.B.
        • Evans D.A.
        • et al.
        A common DIO2 polymorphism and Alzheimer disease dementia in African and European Americans.
        J. Clin. Endocrinol. Metab. 2018; 103: 1818-1826https://doi.org/10.1210/jc.2017-01196
        • Nair S.
        • Muller Y.L.
        • Ortega E.
        • et al.
        Association analyses of variants in the DIO2 gene with early-onset type 2 diabetes mellitus in Pima Indians.
        Thyroid. 2012; 22: 80-87https://doi.org/10.1089/thy.2010.0455
        • Philibert R.A.
        • Beach S.R.
        • Gunter T.D.
        • et al.
        The relationship of deiodinase 1 genotype and thyroid function to lifetime history of major depression in three independent populations.
        Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011; 156: 593-599
        • Cooper-Kazaz R.
        • van der Deure W.M.
        • Medici M.
        • et al.
        Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine.
        J. Affect. Disord. 2009; 116: 113-116https://doi.org/10.1016/j.jad.2008.10.019
        • Brozaitiene J.
        • Skiriute D.
        • Burkauskas J.
        • et al.
        Deiodinases, organic anion transporter polypeptide polymorphisms, and thyroid hormones in patients with myocardial infarction.
        Genet. Test Mol. Biomarkers. 2018; 22: 270-278https://doi.org/10.1089/gtmb.2017.0283
        • Meulenbelt I.
        • Bos S.D.
        • Chapman K.
        • et al.
        Meta-analyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility.
        Ann. Rheum. Dis. 2011; 70: 164-167https://doi.org/10.1136/ard.2010.133660
        • Burkauskas J.
        • Brozaitiene J.
        • Staniute M.
        • et al.
        Gene-environment interactions connecting low triiodothyronine syndrome and outcomes of cardiovascular disease (GET-VASC): study protocol.
        Biol. Psychiatry Psychopharmacol. 2014; 16: 66-73
        • Al-Subaihi A.A.
        Sample size determination. Influencing factors and calculation strategies for survey research.
        Saudi Med. J. 2003; 24: 323-330
        • Hatano S.
        Experience from a multicentre stroke register: a preliminary report.
        Bull. World Health Organ. 1976; 54: 541-553
        • Zhao F.
        • Song M.
        • Wang Y.
        • et al.
        Genetic model.
        J. Cell. Mol. Med. 2016; 20: 765https://doi.org/10.1111/jcmm.12751
        • Sim J.
        • Teece L.
        • Dennis M.S.
        • et al.
        Validation and recalibration of two multivariable prognostic models for survival and independence in acute stroke.
        PLoS One. 2016; 11e0153527https://doi.org/10.1371/journal.pone.0153527
        • Lindgren A.
        • Maguire J.
        Stroke recovery genetics.
        Stroke. 2016; 47: 2427-2434https://doi.org/10.1161/strokeaha.116.010648
        • Mola-Caminal M.
        • Carrera C.
        • Soriano-Tarraga C.
        • et al.
        PATJ low frequency variants are associated with worse ischemic stroke functional outcome.
        Circ. Res. 2019; 124: 114-120https://doi.org/10.1161/circresaha.118.313533
        • Cao L.
        • Zhang Z.
        • Cai B.
        • et al.
        Association of heme oxygenase-1 gene rs2071746 polymorphism with vascular outcomes in patients with atherosclerotic stroke.
        J. Neurol. Sci. 2014; 344: 154-157https://doi.org/10.1016/j.jns.2014.06.046
        • Stepien B.K.
        • Huttner W.B.
        Transport, metabolism, and function of thyroid hormones in the developing mammalian brain.
        Front. Endocrinol. (Lausanne). 2019; 10: 209https://doi.org/10.3389/fendo.2019.00209
        • van der Spek A.H.
        • Fliers E.
        • Boelen A.
        Thyroid hormone metabolism in innate immune cells.
        J. Endocrinol. 2017; 232: R67-r81https://doi.org/10.1530/joe-16-0462
        • Raymaekers S.R.
        • Darras V.M.
        Thyroid hormones and learning-associated neuroplasticity.
        Gen. Comp. Endocrinol. 2017; 247: 26-33https://doi.org/10.1016/j.ygcen.2017.04.001
        • Fanibunda S.E.
        • Desouza L.A.
        • Kapoor R.
        • et al.
        Thyroid hormone regulation of adult neurogenesis.
        Vitam. Horm. 2018; 106: 211-251https://doi.org/10.1016/bs.vh.2017.04.006
        • Li J.
        • Abe K.
        • Milanesi A.
        • et al.
        Thyroid hormone protects primary cortical neurons exposed to hypoxia by reducing DNA methylation and apoptosis.
        Endocrinology. 2019; https://doi.org/10.1210/en.2019-00125
        • Zhang F.
        • Lupski J.R.
        Non-coding genetic variants in human disease.
        Hum. Mol. Genet. 2015; 24: R102-R110https://doi.org/10.1093/hmg/ddv259
        • Hernandez A.
        • Stohn J.P.
        The type 3 deiodinase: epigenetic control of brain thyroid hormone action and neurological function.
        Int. J. Mol. Sci. 2018; 19https://doi.org/10.3390/ijms19061804
        • Tan L.
        • Yu J.T.
        • Tan L.
        Causes and consequences of MicroRNA dysregulation in neurodegenerative diseases.
        Mol. Neurobiol. 2015; 51: 1249-1262https://doi.org/10.1007/s12035-014-8803-9
        • Toffoli M.
        • Dreussi E.
        • Cecchin E.
        • et al.
        SNCA 3'UTR genetic variants in patients with Parkinson's disease and REM sleep behavior disorder.
        Neurol. Sci. 2017; 38: 1233-1240https://doi.org/10.1007/s10072-017-2945-2
        • Sugiyama D.
        • Kusuhara H.
        • Taniguchi H.
        • et al.
        Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine.
        J. Biol. Chem. 2003; 278: 43489-43495https://doi.org/10.1074/jbc.M306933200
        • Shaul O.
        How introns enhance gene expression.
        Int. J. Biochem. Cell Biol. 2017; 91: 145-155https://doi.org/10.1016/j.biocel.2017.06.016
        • Soderholm M.
        • Pedersen A.
        • Lorentzen E.
        • et al.
        Genome-wide association meta-analysis of functional outcome after ischemic stroke.
        . 2019; 92: e1271-e1283https://doi.org/10.1212/wnl.0000000000007138
        • Kido T.
        • Sikora-Wohlfeld W.
        • Kawashima M.
        • et al.
        Are minor alleles more likely to be risk alleles?.
        BMC Med. Genet. 2018; 11: 3https://doi.org/10.1186/s12920-018-0322-5
        • Gorlov I.P.
        • Gorlova O.Y.
        • Amos C.I.
        Allelic spectra of risk SNPs are different for environment/lifestyle dependent versus independent diseases.
        PLoS Genet. 2015; 11e1005371https://doi.org/10.1371/journal.pgen.1005371
        • Russell W.
        • Harrison R.F.
        • Smith N.
        • et al.
        Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels.
        J. Clin. Endocrinol. Metab. 2008; 93: 2300-2306https://doi.org/10.1210/jc.2007-2674
        • Arsava E.
        • Rahman R.
        • Rosand J.
        • et al.
        Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke.
        Neurology. 2009; 72: 1403-1410
        • Belagaje S.R.
        Stroke rehabilitation.
        Continuum (Minneap Minn). 2017; 23: 238-253https://doi.org/10.1212/con.0000000000000423